Acne vulgaris, often referred to simply as acne, is a common skin disease that typically, although not exclusively, affects adolescents. When untreated, most cases of acne persist for several years and then spontaneously remit, usually when an individual is in the mid-twenties.
The etiology of acne is multi-factorial. The disease is thought to originate primarily due to increased production of sebum, hypercornification of the infundibulum of pilosebaceous glands, proliferation of microbial flora especially Propionibacterium acnes, and subsequent inflammation. The normal process of epidermal maturation, called keratinization, involves the growing and shedding of cells that line the pores and glands of the skin. In acne, this process is disrupted, causing an overproduction of epithelial cells (hyperkeratosis) in the follicular infundibulum of the sebaceous gland duct, forming a blockage of the pore.
The resulting lesions can be divided into inflammatory and non-inflammatory lesions. Non-inflammatory lesions, classified as open and closed comedones, are commonly known as blackheads and whiteheads, respectively. Cases of acne presenting solely non-inflammatory lesions are sometimes referred to as mild acne.
Inflammatory lesions are a result of excessive growth of the common bacteria, Propionibacterium acnes, and its interaction with the normal oils of the skin (sebum), resulting in the generation of byproducts that elicit an inflammatory reaction. In addition to these primary lesions, patients may also suffer from scars as a complication of inflammatory lesions.
Inflammatory lesions of acne may be divided into two groups. Less severe cases of acne are associated with pustules and papules, as well as with non-inflammatory lesions. Papules are inflamed, red, tender bumps with no head that range from 2 to 5 mm in diameter. Pustules are papules that are superficial and contain grossly purulent material, that is they have a head with a white or yellow center. Depending on the number of papules and pustules present, papulopustular acne cases may be graded in a range from moderate to severe acne. Individuals with severe cases of papulopustular acne may also have one or two acne nodules or cysts.
More severe cases of acne are associated with nodules and cysts as a predominant lesion. Such individuals present with three or more nodules and typically also have multiple other inflammatory lesions, such as pustules and papules, and non-inflammatory lesions, such as comedones. Cysts and nodules are blockages of the oil glands of the skin that have burst open and produced inflammation and pus in the surrounding tissues. Nodules are large, hard bumps 5 mm or more in diameter present under or within the surface of the skin, which can be painful and can last for many months. Cysts are similar to nodules but are pus-filled. Cases of acne presenting with inflammatory acne with cysts and/or nodules are often referred to as severe acne. However, since there is no accepted definition for the term “severe acne” and often papular or pustular acne is referred to as severe acne, it is preferred to refer to cases of acne presenting with cysts and/or nodules by the more specific term of “nodular” acne.
The Food and Drug Administration has recognized that nodular acne is a distinct entity that is to be considered independently of other, milder forms of acne. In the Draft Guidance for Industry—Acne Vulgaris: Developing Drugs for Treatment, issued in September 2005 by the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), the IGA Scale for Acne Vulgaris was utilized to grade the severity of non-nodular acne for the purposes of clinical trials of topical drugs. The IGA Scale for Acne Vulgaris, as depicted in the Draft Guidance for Industry, is as shown in Table 1.
TABLE 1GradeDescription0Clear skin with no inflammatory or noninflammatory lesions1Almost clear; rare noninflammatory lesions with no morethan one small inflammatory lesion2Mild severity; greater than Grade 1; some noninflammatorylesions with no more than a few inflammatory lesions(papules/pustules only, no nodular lesions)3Moderate severity; greater than Grade 2; up to manynoninflammatory lesions and may have some inflammatorylesions, but no more than one small nodular lesion4Severe; greater than Grade 3; up to many noninflammatory andinflammatory lesions, but no more than a few nodular lesions
In the Draft Guidance for Industry, immediately below the IGA Scale, the FDA further distinguishes nodulocystic acne from other forms of acne and states that, “It is recommended that enrollment of acne vulgaris patients not include patients with nodulocystic acne.” The Draft Guidance for Industry also states that because there are specific information needs with regard to treatment for nodular acne, applicants should seek additional guidance from the FDA regarding treatments that are targeted for nodular/nodulocystic acne.
Mild acne is typically treated with topical cleansers and benzoyl peroxide. Moderate inflammatory acne is often treated with cleansers and keratolytic or comedolytic agents such as retinoids (tretinoin, adapalene or tazaratene), salicylic acid or alphahydroxy acids, often in combination with topical or systemic antibiotics. Systemic antibiotics, including tetracycline, minocycline, doxycycline, erythromycin, and azithromycin, have been used successfully to treat pustular or papular acne. In May 2006, the Food and Drug Administration approved SOLODYN™ (minocycline HCl, Medicis Pharmaceutical Corp., Scottsdale, Ariz.) for treatment of non-nodular moderate to severe acne. The prescribing information on the package insert for Solodyn™ as approved by the FDA specifically states that “Solodyn™ is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgarism” To date, no antibiotic has been shown to be effective or has been approved by the FDA for treatment of nodular acne.
In cases of nodular acne, a dermatologist will often prescribe isotretinoin (ACCUTANE®, Roche Laboratories, Inc., Nutley, N.J.). Isotretinoin has been found to be effective in clearing nodular acne lesions. The drug works by reducing the size of oil glands in the skin so that much less oil is produced and the growth of bacteria is decreased.
The use of isotretinoin, however, has severe disadvantages. Isotretinoin has been shown to cause birth defects in the developing fetus and, therefore, pregnant women should not use isotretinoin. Additionally, isotretinoin has been associated with depression and suicidal thoughts in users. Because of the dangers associated with the use of isotretinoin, the FDA has initiated a program to permit only registered pharmacies and health care providers to dispense isotretinoin and to closely monitor the prescriptions and any adverse reactions occurring in patients receiving isotretinoin.
Because of the severe side effects of isotretinoin, there is currently no safe, approved therapy for treating nodular acne vulgaris.
Pigatto et al, “Isotretinoin versus Minocycline in Cystic Acne: A Study of Lipid Metabolism”, Dermatologica, 172:154-159 (1986) compared the efficacy of treatment of nodular cystic acne with isotretinoin and with minocycline, a member of the tetracycline family of antibiotics. Pigatto found that isotretinoin was highly efficacious in treating nodular cystic acne. In contrast, Pigatto found that, although minocycline was initially effective in reducing the number and size of nodules and cysts, treatment with minocycline beyond 4 weeks resulted in no further improvement. Moreover, treatment with minocycline did not, at any time during the study, decrease the number or size of cysts to a level that would be considered to be less than severe. As shown in FIG. 1 of Pigatto, treatment with minocycline reduced the number of cysts from an average of 20 to 10 during the first 10 weeks of treatment, but that further treatment with minocycline did not further decrease the number of cysts in the patients. Likewise, initial 10 week treatment with minocycline reduced the average diameter of cysts from 15 mm to 8 mm, but further treatment failed to produce any further reduction in diameter. In fact, after 20 weeks of treatment, average cyst diameter had increased once again to 10 mm. The Pigatto study establishes that minocycline is not an effective therapy for treatment of nodular acne.
The question of whether minocycline could be an effective therapeutic agent for nodular acne when used in combination with an additional anti-acne therapy was studied in Gollnick et al, “Comparison of Combined Azaleic Acid Cream Plus Oral Minocycline with Oral Isotretinoin in Severe Acne”, Eur. J. Dermatol., 11:538-544 (2001). Golinick evaluated patients treated for six months with a combination of oral minocycline and topically applied azaleic acid cream and found that treatment after two months with this combination resulted in a decrease of 60% in number of deep acne lesions (cysts and nodules) and a decrease of 100% after four months. Thus, minocycline is an effective therapy for nodular acne when combined with topically applied azaleic acid.
The mode of action of minocycline and other tetracycline antibiotics in treating lesions of acne is uncertain. Ashley, U.S. Patent Application Publication No. 2004/0147492 discloses that tetracycline compounds, including minocycline and doxycycline, are effective in treating acne when administered to an individual in an amount that has substantially no antibiotic effect. The data of Ashley indicates that it is something other than the antibiotic effect of these drugs that provides the favorable anti-acne effect, although what the anti-acne mode of action of the tetracyclines is has not been determined. Because it is not the antibiotic activity of these compounds that provides their anti-acne effect, it is clear that one cannot extrapolate the level of effectiveness of tetracycline antibiotics in the treatment of acne to antibiotics that are not members of the tetracycline family.
Azithromycin is the generic name for 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, a broad spectrum antibiotic derived from erythromycin A. It was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel, U.S. Pat. No. 4,517,359, where it was referred to by the name of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A. Bright and Kobrehel disclosed azithromycin as a hygroscopic form. Allen, U.S. Pat. No. 6,268,489, discloses a non-hygroscopic dihydrate form of azithromycin. Both the monohydrate form and the dihydrate form are effective in treating bacterial infections when administered systemically.
Several scientific articles have published studies concerning the efficacy of azithromycin in treating lesions of inflammatory acne. Fernandez-Obregon, “Azithromycin for the Treatment of Acne,” International Journal of Dermatology, 39:45-50 (2000), discloses that azithromycin administered in a pulse-dose regimen is as effective as other antibiotics tested in treating lesions of inflammatory acne.
Fernandez-Obregon compared daily systemic administration of doxycycline, erythromycin, minocycline, and tetracycline to three-times-weekly administration of azithromycin and found that the azithromycin treatment regimen was as effective as the daily treatment regimens of the other antibiotics in treating the lesions of inflammatory acne, even though azithromycin was administered at a much lower frequency than were the other antibiotics.
Treatment of acne with azithromycin, rather than with minocycline or doxycycline, is desirable because of the broad range of deleterious side effects that are experienced by users of minocycline and doxycycline. Minocycline use has been associated with skin discoloration, central nervous system effects such as dizziness and pseudomotor cerebri, and a lupus-like syndrome. Doxycycline use has been associated with gastrointestinal upsets, erosive esophagitis and photosensitivity. Both minocycline and doxycycline are also associated with candida vaginitis. Although there is some question as to whether azithromycin use may cause candida vaginitis, azithromycin has not been known to cause any of the other above side effects associated with minocycline or doxycycline. Additionally, minocycline and doxycycline are placed in Pregnancy Category D, which includes drugs that have some significant risks and that should be used during pregnancy only when the alternatives are worse. In contrast, azithromycin is a Pregnancy Category B drug, which category includes drugs that are used routinely and safely during pregnancy and which are considered safe to use if there is a clinical need for the drug.
The Fernandez-Obregon study treated patients suffering from at least 12 lesions of inflammatory acne, defined as papules, pustules, or cysts. Patients were graded on the reduction of the number of lesions associated with each treatment. The Fernandez-Obregon article did not distinguish between the various types of inflammatory lesions and it is possible, if not likely, that none of the patients treated had nodular or cystic lesions, or had at most one or two such lesions. Also, because nodular or cystic acne is considered to be a distinct form of acne requiring specific therapy and the intent of the Fernandez-Obregon study was to compare the efficacy of azithromycin to that of other antibiotics, which are known in the art to be efficacious to treat papular and pustular inflammatory lesions but not nodular or cystic lesions, it is evident to one of skill of the art that the patients treated in the Fernandez-Obregon study, although possibly having one or two cystic lesions, would not have been included in the study if they had been suffering from a distinct and more severe nodular acne.
A similar study was reported by Singhi, MK, et al, “Comparison of Oral Azithromycin Pulse with Daily Doxycycline in the Treatment of Acne Vulgaris,” Indian Journal of Dermatology, Venereology, and Leprology, 69(4):274-276 (2003). Singhi compared azithromycin given at a dose of 500 mg for three consecutive days in a 10 day cycle with doxycycline given daily to a population of individuals suffering from moderate to severe inflammatory acne. Each of the individuals also received topical erythromycin therapy throughout the study.
Each of the patients was graded for severity of acne prior to commencement of therapy and at the end of therapy. The severity of acne was graded counting the number of comedones, papules, pustules, infiltrated, and cystic lesions, multiplying the number of each type of lesion by the lesions severity index (0.5 for comedones, 1 for papule, 2 for pustule, 3 for infiltrated lesion, and 4 for cyst), and summing the results.
Like Fernandez-Obregon, Singhi does not disclose that any of the subjects studied suffered from nodular acne and there is no suggestion that any of the subjects had multiple acne nodules. The results of Singhi were disclosed to be similar to those of Fernandez-Obregon and showed that azithromycin is an effective medication for treating moderate to severe acne vulgaris.
It is clear from the disclosures of Fernandez-Obregon and Singhi that nodular acne was not treated in their studies. Because an effective therapy for nodular acne that does not produce the severe side effects of isotretinoin has long been sought, if either of these studies had shown an effective antibiotic therapy against nodular or cystic acne, this result would have been proclaimed clearly as a breakthrough in acne therapy.
Accordingly, the need persists to the present day for an effective therapy for nodular acne that does not present severe side effects, such as those that occur with isotretinoin and possibly with tetracycline family antibiotic therapy.